EP0323855B1 - Pantéthine comme agent inhibiteur de la fibrose hépatique - Google Patents

Pantéthine comme agent inhibiteur de la fibrose hépatique Download PDF

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Publication number
EP0323855B1
EP0323855B1 EP89100180A EP89100180A EP0323855B1 EP 0323855 B1 EP0323855 B1 EP 0323855B1 EP 89100180 A EP89100180 A EP 89100180A EP 89100180 A EP89100180 A EP 89100180A EP 0323855 B1 EP0323855 B1 EP 0323855B1
Authority
EP
European Patent Office
Prior art keywords
pantethine
hepatic fibrosis
liver
inhibitory agent
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89100180A
Other languages
German (de)
English (en)
Other versions
EP0323855A2 (fr
EP0323855A3 (en
Inventor
Munehiro Tomikawa
Junichiro Wakasugi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Pharmaceutical Co Ltd
Original Assignee
Daiichi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Pharmaceutical Co Ltd filed Critical Daiichi Pharmaceutical Co Ltd
Publication of EP0323855A2 publication Critical patent/EP0323855A2/fr
Publication of EP0323855A3 publication Critical patent/EP0323855A3/en
Application granted granted Critical
Publication of EP0323855B1 publication Critical patent/EP0323855B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Definitions

  • This invention relates to the use of pantethine as an active ingredient for preparing a pharmaceutical composition for treating hepatic fibrosis.
  • Hepatic fibrosis means an abnormal increase in fibrous connective tissue following hepatic diseases such as alcoholic hepatitis. Hepatic fibrosis induces excessive deposition of connective tissue such as collagen and, at the same time, causes dysfunction of the liver. The progressing of hepatic fibrosis finally causes cirrhosis.
  • Pantethine (D-bis-(N-pantothenyl- ⁇ -aminoethyl)-disulfide) has been reported to be effective on hepatic diseases such as medicinal fatty liver in JP-B-No. 60-19891 (the term “JP-B” as used herein means an "examined published Japanese patent application), JP-A-55-76816 and Med. Pharm. 1979, 13(1), 34-38 and viral hepatitis in JP-A-No. 58-35118 (the term “JP-A” as used herein means an "unexamined published Japanese patent application”).
  • JP-B as used herein means an "examined published Japanese patent application
  • JP-A-55-76816 and Med. Pharm. 1979, 13(1), 34-38
  • JP-A as used herein means an "unexamined published Japanese patent application”
  • This invention therefore relates to the use of pantethine as an active ingredient for preparing a pharmaceutical composition for treating hepatic fibrosis.
  • Pantethine is a compound of high safety, and the acute toxicity (LD50) thereof in mice is over 10 g/kg-body weight (p.o.).
  • Dosage forms of the inhibitory agent of hepatic fibrosis according to the present invention include tablets, powders, granules, capsules, injectable solutions.
  • dosage forms can be prepared using conventional pharmaceutical techniques by combining pantethine, the main ingredient, with vehicles (e.g., starch, cellulose), disintegrators, stabilizers.
  • vehicles e.g., starch, cellulose
  • the agent of the invention is usually administered orally or parenterally at a dose level of from 200 to 2,000 mg/day for an adult (about 60 kg body weight) in oral administration.
  • the main component of fibrous connective tissue playing an important role in hepatic fibrosis is collagen, and it is known that collagen synthesis is accelerated during the progression of hepatic fibrosis. It is also known that prolyl hydroxylase acts as a rate limiting enzyme in collagen synthesis and the increase in the activity of the enzyme in the liver is closely correlated with the appearance and progression of hepatic fibrosis.
  • the agent of the present invention significantly inhibited an increase in prolyl hydroxylase activity in the liver of a hepatic fibrosis model induced by cholesterol-feeding.
  • the agent of the present invention is therefore excellent as an inhibitory agent of hepatic fibrosis.
  • a cholesterol group consisting of 8 rabbits were fed on RC-4 diet (sold by Oriental Kobo Co., Ltd.) containing 0.5% cholesterol for 10 weeks.
  • a pantethine group consisting of 9 rabbits were fed on RC-4 diet containing 0.5% cholesterol and 1% pantethine for 10 weeks.
  • a control group consisting of 3 rabbits were fed on RC-4 diet for the same period.
  • the rabbits were sacrificed by exsangination from abdominal aorta under anesthesia with pentobarbital and the liver and kidney were removed. A portion of the organ was homogenized with 9 times the volume of a 0.01M Trishydrochloric acid buffer solution (pH 7.4) containing 10 ⁇ 5M EDTA and 10 ⁇ 4M DTT in Polytron homogenizer.
  • the prolyl hydroxylase activity was expressed as radioactivity of 3H2O released per milligram of protein when 3H-proline labeled unhydroxylated collagen was incubated as a substrate for 30 minutes. That is, 800 ⁇ l of a substrate mixture having the composition shown in Table 1 below was added to 200 ⁇ l of the homogenate. Incubation was carried out at 30°C for 30 minutes.
  • the prolyl hydroxylase activity in the liver of the cholesterol group significantly increased to about 2.6 times the level of the normal group.
  • This stimulation of the activity of prolyl hydroxylase indicates that cholesterol-feeding induced an increase in collagen synthesis, and hepatic fibrosis was observed in the cholesterol group.
  • the prolyl hydroxylase activity in the liver of the pantethine group was decreased nearly to the level of the normal group by administering pantethine. Pantethine was thus proved inhibitory on hepatic fibrosis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (1)

  1. Utilisation de pantéthine en tant que principe actif pour la préparation d'une composition pharmaceutique destinée à traiter la fibrose hépatique.
EP89100180A 1988-01-06 1989-01-05 Pantéthine comme agent inhibiteur de la fibrose hépatique Expired - Lifetime EP0323855B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1067/88 1988-01-06
JP106788 1988-01-06

Publications (3)

Publication Number Publication Date
EP0323855A2 EP0323855A2 (fr) 1989-07-12
EP0323855A3 EP0323855A3 (en) 1990-12-05
EP0323855B1 true EP0323855B1 (fr) 1994-04-13

Family

ID=11491185

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89100180A Expired - Lifetime EP0323855B1 (fr) 1988-01-06 1989-01-05 Pantéthine comme agent inhibiteur de la fibrose hépatique

Country Status (8)

Country Link
US (1) US4937266A (fr)
EP (1) EP0323855B1 (fr)
KR (1) KR970005324B1 (fr)
AU (1) AU614569B2 (fr)
CA (1) CA1318254C (fr)
DE (1) DE68914468T2 (fr)
ES (1) ES2054881T3 (fr)
PH (1) PH26554A (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02232670A (ja) * 1989-03-06 1990-09-14 Minolta Camera Co Ltd 複写機
US6046219A (en) * 1995-01-20 2000-04-04 Cornell Research Foundation, Inc. Method for the treatment of conditions mediated by collagen formation together with cell proliferation by application of inhibitors of protein hydroxylation
US5789426A (en) * 1995-01-20 1998-08-04 Cornell Research Foundation, Inc. Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation
US5965621A (en) * 1995-08-17 1999-10-12 Allergan Methods and compositions for reducing or maintaining body weight in a mammal
WO2002098405A1 (fr) * 2001-06-05 2002-12-12 Ajinomoto Co., Inc. Inhibiteurs de fibrose du foie
PL1734970T3 (pl) 2004-03-12 2015-05-29 Intercept Pharmaceuticals Inc Leczenie zwłóknienia z zastosowaniem ligandów FXR
HRP20171873T1 (hr) 2013-02-07 2018-02-23 Scifluor Life Sciences, Inc Fluorinirani antagonisti integrina
KR102647026B1 (ko) 2015-02-19 2024-03-12 사이플루어 라이프 사이언시즈, 인크 플루오르화 테트라히드로나프티리디닐 노난산 유도체 및 이의 용도
KR20170141757A (ko) 2015-04-30 2017-12-26 사이플루어 라이프 사이언시즈, 인크 테트라하이드로나프티리디닐 프로피온산 유도체 및 이의 용도
WO2017189828A1 (fr) 2016-04-27 2017-11-02 Scifluor Life Sciences, Inc. Dérivés d'acide nonanoïque et décanoïque et leurs utilisations

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2110536B (en) * 1981-12-04 1986-10-29 Sogo Pharm Pharmaceutical compositions containing pantetheine-s-sulphonic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
The Merck Manual, 15th ed., 1987, p. 850-855 *

Also Published As

Publication number Publication date
CA1318254C (fr) 1993-05-25
KR890011588A (ko) 1989-08-21
AU2772389A (en) 1989-07-13
ES2054881T3 (es) 1994-08-16
PH26554A (en) 1992-08-19
KR970005324B1 (ko) 1997-04-15
US4937266A (en) 1990-06-26
EP0323855A2 (fr) 1989-07-12
EP0323855A3 (en) 1990-12-05
DE68914468T2 (de) 1994-07-28
AU614569B2 (en) 1991-09-05
DE68914468D1 (de) 1994-05-19

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